Benzofuranylimidazole derivatives, a process for their preparation and therapeutical compositions containing the same

ABSTRACT

The invention relates to benzofuranylimidazole derivatives of the general formula (1) ##STR1## wherein R 1  and R 2  represent various radicals, to a process for their preparation and to pharmaceutical compositions containing them.

This invention relates to new benzofuranylimidazole derivatives, to aprocess for their preparation and to pharmaceutical compositionscontaining them. The imidazole derivatives of this invention have a highselectivity for the imidazoline receptors.

The invention provides benzofuranylimidazole derivatives of the generalformula (1) ##STR2## wherein

R₁ represents an hydrogen atom or an alkyl group having from 1 to 6carbon atoms, and

R₂ represents an hydroxy group or R'₂ wherein R'₂ represents an hydrogenatom, an halogen atom, an alkyl group having from 1 to 6 carbon atoms,or an alkoxy group having from 1 to 5 carbon atoms; and further providespharmaceutically acceptable salts of such derivatives. Said salts may bethose formed with both organic and inorganic acids such as hydrochloric,sulfuric, phosphoric, acetic, citric, propionic, malonic, succinic,fumaric, tartaric, cinnamic, methanesulfonic and p-toluene-sulfonicacids, and preferably hydrochloric acid.

Some series of benzofuranylimidazoline derivatives have been describedin the literature. Thus, in Indian J. Chem. 1979, 18B, 254, has beendisclosed the following compound ##STR3## This compound was evaluatedfor antibacterial and antifungal activity without showing any noteworthyactivity. In the U.S. Pat. No. 3,927,023 have been disclosed compoundsof the following formula ##STR4## indicated for the treatment of gastriculcers. Recently, it has been described that some α₂ -adrenoceptorantagonists also show affinity for the so-called "imidazoline receptor"(see for instance: Laugien et al., Mol. Pharmacol. 1990, 37, 876). Theimidazoline receptors are related with the regulation of blood pressure,modulation of insulin release and other biological functions (see forinstance: Bousquet et al., Am. J. Med. 1989, (supp 3C), 105). Moreover,it seems that the imidazoline compounds are able to inhibit thenoradrenaline release in aorta and pulmonary arteries, involvingpurinoceptors P₁ and prostaglandin receptors (see for instance: Gothertet al., Naunyn-Schmied. Arch. Pharmacol. 1991, 343, 271).

The compounds of the invention possess affinity for imidazolinereceptors and very low affinity for the α₂ -adrenergic receptors.

The invention also provides a process for the preparation of compoundsof the general formula (1), the process comprising the two followingsuccessive steps:

reacting a compound of the general formula (2) ##STR5## wherein R'₂ isas above defined, R represents an alkyl group having from 1 to 4 carbonatoms and HX represents an acid,

with, at least, one molar equivalent of the aminoacetaldehyde dialkylacetal, in a polar solvent, for 1 to 24 hours, at a temperature of from-5° C. to the boiling point of the reaction mixture, and

cyclising, in an aqueous acidic medium, for 1 to 24 hours, at atemperature of from 15° to 80° C., the resultant compound of the generalformula (3) ##STR6## wherein R' and R" represent, each, an alkyl grouphaving from 1 to 4 carbon atoms, which lead to compounds of the generalformula (1) wherein R₁ represents an hydrogen atom and R₂ representsR'₂.

For the preparation of compounds of the general formula (1) wherein R₁represents an alkyl group, the process of the invention comprises thetwo further steps consisting of the treatment of the compounds of thegeneral formula (1) wherein R₁ represents a hydrogen atom, by a base, inan aprotic solvent, at a temperature of from -10° to 25° C., followed bythe treatment by the appropriate alkyl-halide or alkyl sulfonate.

For the preparation of compounds of the general formula (1) wherein R₂represents an hydroxy group, the process of the invention comprises afurther step consisting of the treatment of the compound of the generalformula (1) wherein R'₂ represents an alkoxy group, by a dealkylatingagent.

In the compounds (2), R preferably represents a methyl or ethyl groupand HX preferably represents hydrochloric acid. The aminoacetaldehydedialkyl acetal with which this compound is reacted is preferablydimethyl- or diethyl-acetal. The reaction is preferably conducted in apolar solvent, such as methanol or ethanol. More preferably, thereaction is conducted for 15-17 hours in refluxing methanol.

In the compounds (3), R' and R" preferably represent a methyl or ethylgroup. More preferably, the compounds are heated at 40°-60° C. for 16-20hours in 10% aqueous hydrochloric acid.

The base used in the conversion of the compounds (1) in which R₁represents an hydrogen atom to the compounds (1) in which R₁ representsan alkyl group, is preferably sodium hydride. The reaction may beconducted in an aprotic solvent such as dimethylformamide (DMF),preferably at 0° C.

The dealkylating agent used in the conversion of the compound (1) inwhich R₂ represents an alkoxy group to compounds (1) in which R₂represents an hydroxy group, is preferably selected from withintrimethylsilyl iodide and aqueous hydrogen bromide.

The compounds of general formula (2) may be prepared from thecorresponding cyano compounds of the general formula (4) ##STR7## bytreatment with an alcohol of the formula ROH wherein R is as abovedefined, in the presence of an HX acid. Most conveniently the alcoholused is methanol and HX used is hydrogen chloride.

The cyano compounds (4) may in turn be prepared from the correspondingcarboxylic acid of the general formula (5) ##STR8## by treatment with ahalogenating agent and subsequent reaction with ammonia, followed bydehydration with phosphorous pentoxide. The acids (5) are obtainedaccording to the method described in J. Am. Chem. Soc. 1951, 73, 872.

Finally, the invention provides a pharmaceutical composition comprisinga benzofuranylimidazole derivative of the general formula (1) as abovedefined or a pharmaceutically acceptable salt of such a derivative inadmixture with a pharmaceutically acceptable diluent or carrier.

The following examples illustrate the invention. In these examples, thevarious compounds and intermediates were characterised by their NMRspectra recorder on a Varian Gemini 200 spectrometer at 200 MHz for ¹ Hand at 50 MHz for ¹³ C and are reported in ppm downfield from theresonance of tetramethylsilane. Melting points were measured on a Buchimelting point apparatus in glass capillary tubes and are uncorrected. IRspectra were recorder on a Nicolet 5PC FT-IR spectrophotometer.

EXAMPLE 1 2-(benzofuran-2-yl)imidazole hydrochloride R₁ =H R₂ =H

a) preparation of benzofuran-2-carbonyl chloride

Thionyl chloride (12.5 ml) was added to a suspension ofbenzofuran-2-carboxylic acid (20 g) in anhydrous benzene (250 ml). Themixture was refluxed for 3 hours, then allowed to cool down to roomtemperature. Removal of the volatiles left the desired acid chloride(21.8 g, 98%).

b) preparation of benzofuran-2-carboxamide

Benzofuran-2-carbonyl chloride (21.8 g) was added in small portions toan ice cold solution of ammonia (200 ml, d=0.91). Upon completion of theaddition the reaction mixture was allowed to reach room temperature andthe desired carboxamide formed a precipitate. The solid was collected byfiltration, washed with water and dried in vacuo (17.8 g, 91%). IR:(KBr): 1661 cm⁻¹

¹ H-NMR (DMSO-d₆): 7.35 (t,1H), 7.45 (t,1H), 7.60 (s,1H), 7.65 (d,1H),7.75 (d,1H), 7.70-8.20 (d,2H).

c) preparation of 2-cyanobenzofuran

Phosphorus pentoxide (86 g) was added to a suspension ofbenzofuran-2-carboxamide (17.8 g) in anhydrous toluene (500 ml) and themixture was refluxed for 3 hours. After cooling the supernating solutionwas decanted off and the resulting residue extracted with toluene. Thecombined toluene fractions were evaporated to leave the cyano compoundas an oil (10.7 g, 68%). IR: (NaCl): 2231 cm⁻¹

¹ H-NMR (DMSO-d₆): 7.45 (t,1H), 7.55 (t,1H), 7.75 (d,1H), 7.85 (d,1H),8.10 (s,1H).

d) preparation of methyl benzofuran-2-carboximidate hydrochloride

2-Cyanobenzofuran (10.7 g) was dissolved in ethereal HCl (150 ml, 5M)and methanol (12 ml). The resulting mixture was kept at 4° C. for 48hours. The resulting solid was filtered, washed with ether and dried(13.4 g, 85%).

¹ H-NMR (DMSO-d₆): 4.30 (s,3H), 7.50 (t,1H), 7.70 (t,1H), 7.80 (d,1H),7.90 (d,1H), 8.40 (s,1H).

e) preparation of 2-(benzofuran-2-yl)-imidazole hydrochloride

A solution of aminoacetaldehyde dimethylacetal (7.3 g) and methylbenzofuran-2-carboximidate hydrochloride (13.4 g) in methanol (135 ml)was stirred at 60° C. for 16 hours. The mixture was then evaporated todryness. Hydrochloric acid (750 ml, 2M) was added and the resultingmixture was stirred at 60° C. for 16 hours. After cooling, the solutionwas washed with dichloromethane. The aqueous layer was basified withsodium hydroxide and the free base was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried. Evaporation ofthe solvent gave a solid residue which was dissolved in diethylether/ethanol. Ethereal HCl was added to solution and the precipitatedsalt was collected by filtration (12.5 g, 90%).

m.p.=225°-227° C.

¹ H-NMR (DMSO-d₆): 7.40 (t,1H), 7.50 (t,1H), 7.75 (d,1H), 7.85 (s,2H),7.90 (d,1H), 8.20 (s,1H).

¹³ C-NMR (DMSO-d₆): 110.4, 112.1, 121.2, 123.4, 124.9, 127.6, 127.8,135.4, 141.1, 155.1

EXAMPLE 2 1-methyl-2-(benzofuran-2-yl)imidazole hydrochloride R₁ =CH₃ --R₂ =H

To a solution of the free base (7.0 g) generated from2-(benzofuran-2-yl)imidazole hydrochloride in DMF (50 ml) at 0° C. wasadded sodium hydride (1.4 g) 80% in mineral oil in three equal portions.After 30 minutes at room temperature, methyl iodide (2.5 ml) was addeddropwise over 15 minutes at 0° C. The mixture was then stirred for 30minutes at room temperature, poured into water and extracted with ethylacetate. The organic layer was washed with water and the product wasextracted with hydrochloric acid (1M). The aqueous layer was basifiedwith sodium hydroxide and the free base was extracted with ethylacetate, washed with saturated brine and dried. Evaporation of thesolvent gave a solid residue which was dissolved in diethylether/ethanol. Ethereal HCl was added to solution and the precipitatedsalt was collected by filtration (8.1 g, 91%).

m.p=232°-235° C.

¹ H-NMR (DMSO-d₆): 4.20 (s,3H), 7.45 (t,1H), 7.55 (t,1H), 7.80 (d,1H),7.90 (d,1H), 8.00 (d,1H), 8.20 (s,1H).

¹³ C-NMR (DMSO-d₆): 38.4, 112.0, 112.2, 120.3, 123.3, 125.0, 126.1,127.2, 128.0, 135.2, 140.2, 155.0.

EXAMPLE 3 2-(6-methoxybenzofuran-2-yl)imidazole hydrochloride R₁ =H R₂=6-methoxy

This was prepared from 6-methoxybenzofuran-2-carboxylic acid accordingto the methods a-e as described in example 1; m.p.=245°-248° C.

¹ H-NMR (DMSO-d₆): 3.90 (s,3H), 7.05 (dd,1H), 7.25 (d,1H), 7.75 (d,1H),7.80 (s,2H), 8.10 (s,2H).

¹³ C-NMR (DMSO-d₆): 56.1, 96.2, 110.7, 114.2, 120.6, 120.8, 123.6,135.6, 140.0, 156.5, 160.4.

EXAMPLE 4 2-(6-hydroxybenzofuran-2-yl)imidazole hydrochloride R₁ =H R₂=6-hydroxy

The free base (3.0 g) generated from2-(6-methoxy-benzofuran-2-yl)imidazole hydrochloride was treated with47% w/v hydrobromic acid solution (30 ml) and the mixture heated at 100°C. for 7 hours with stirring. After cooling the resulting solid wasfiltered, dissolved in water and basified with sodium bicarbonate. Thefree base was extracted with ethyl acetate, washed with saturated brineand dried. Evaporation of the solvent gave a solid residue which wasdissolved in diethyl ether/ethanol. Ethereal HCl was added to solutionand the precipitated salt was collected by filtration (2.2 g, 66%).

¹ H-NMR (DMSO-d₆): 6.95 (dd,1H), 7.10 (d,1H), 7.65 (d,1H), 7.80 (s,2H),8.00 (s,1H).

¹³ C-NMR (DMSO-d₆): 97.9, 110.8, 114.8, 119.4, 120.7, 123.6, 135.9,139.2, 156.7, 158.9.

EXAMPLE 5 1-ethyl-2-(benzofuran-2-yl)imidazole hydrochloride R₁ =C₂ H₅-- R₂ =H

This was prepared from 2-(benzofuran-2-yl)imidazole hydrochloride andethyl bromide according to the procedure of example 2; m.p.=183°-185° C.¹ H-NMR (DMSO-d₆): 1.55 (t,3H), 4.60 (q,2H), 7.45 (t,1H), 7.55 (t,1H),7.80 (d,1H), 7.90 (d,1H), 7.95 (d,1H), 8.10 (d,1H), 8.20 (s,1H).

¹³ C-NMR (DMSO-d₆): 15.4, 44.6, 112.2, 112.2, 121.0, 123.2, 124.4,124.9, 127.1, 127.9, 134.4, 140.1, 155.1.

EXAMPLE 6 2-(5-bromobenzofuran-2-yl)imidazole hydrochloride R₁ =H R₂=5-bromo

This was prepared from 5-bromobenzofuran-2-carboxylic acid according tothe methods a-e as described in example 1; m.p.=280° C.

¹ H-NMR (DMSO-d₆): 7.65 (dd,1H), 7.75 (d,1H), 7.85 (s,2H), 8.10 (s,1H),8.15 (d,1H).

¹³ C-NMR (DMSO-d₆): 109.3, 114.1, 117.1, 121.6, 125.8, 129.9, 130.3,135.0, 142.5, 154.0.

EXAMPLE 7 2-(5-methoxybenzofuran-2-yl)imidazole hydrochloride R₁ =H R₂=5-methoxy

This was prepared from 5-methoxybenzofuran-2-carboxylic acid accordingto the methods a-e as described in example 1; m.p.=232°-235° C.

¹ H-NMR (DMSO-d₆): 3.80 (s,3H), 7.10 (dd,1H), 7.40 (d,1H), 7.65 (d,1H),7.80 (s,2H), 8.10 (s,1H).

¹³ C-NMR (DMSO-d₆): 56.0, 104.7, 110.3, 112.7, 116.9, 121.2, 128.3,135.6, 141.8, 150.0, 157.0.

EXAMPLE 8 2-(5-hydroxybenzofuran-2-yl)imidazole hydrochloride R₁ =H R₂=5-hydroxy

This was prepared from the free base generated from2-(5-methoxybenzofuran-2-yl)imidazole hydrochloride according to theprocedure of example 4.

¹ H-NMR (DMSO-d₆): 7.00 (dd,1H), 7.15 (d,1H), 7.55 (d,1H), 7.80 (s,2H),8.00 (s,1H).

¹³ C-NMR (DMSO-d₆): 106.8, 110.3, 112.4, 117.1, 121.1, 128.4, 135.7,141.2, 149.4, 155.1.

EXAMPLE 9 1-ethyl-2-(6-methoxybenzofuran-2-yl)imidazole hydrochloride R₁=C₂ H₅ -- R₂ =6-methoxy

This was prepared from 2-(6-methoxybenzofuran-2-yl)imidazolehydrochloride and ethyl bromide according to the procedure of example 2;m.p.=259°-261° C.

¹ H-NMR (DMSO-d₆): 1.50 (t,3H), 3.90 (s,3H), 4.50 (q,2H), 7.15 (dd,1H),7.35 (d,1H), 7.75 (d,1H), 7.85 (d,1H), 7.95 (d,1H), 8.10 (s,1H).

¹³ C-NMR (DMSO-d₆): 15.4, 44.4, 56.1, 96.0, 112.2, 114.5, 120.1, 120.5,123.3, 123.8, 134.5, 138.8, 156.3, 160.2.

The pharmacological activities of the compounds of the invention havebeen determined according to the following procedures.

Binding studies

Initial biological evaluation of alpha₁ - and alpha₂ -adrenoceptor andimidazoline preferring receptor (IR) affinities and selectivities inhomogenized rat cerebral cortex were assessed by determining the K_(i)values of the compounds to displace ³ H-prazosin ³ H-clonidine as wellas ³ H-idazoxan in the presence of (-)-adrenaline according to themethod of Olmos et al. (J. Neurochem. 1991, 57:1811-1813).

This in vitro model is particularly useful as an initial screening forstudying the affinity and the selectivity of these compounds on theimidazoline receptors. The K_(i) (nM) values of the tested compounds todisplace the binding of ³ H-idazoxan (4 nM) in the presence of(-)-adrenaline (10⁻⁶ M) (IR affinity), ³ H-clonidine (2 nM) and ³H-prazosin (0.5 nM), (alpha₂ - and alpha₁ -adrenoceptors affinityrespectively), are summarized in table 1; this table shows the potentialaffinities and selectivities of compounds and two standard drugsregarding these receptors.

Furthermore, the affinities of compounds of the invention for otherreceptors were also evaluated by determining the K_(i) values ofcompounds to displace the binding of ³ H-pyrilamine (1.1 nM) and ³H-tiotidine (11.8 nM) in homogenized guinea-pig cerebral cortex (H₁ andH₂ histamine receptors, respectively). The K_(i) values for thesecompounds resulted to be higher than 10 μM in both subtypes of histaminereceptors.

In vivo activity

At present, certain compounds of the invention (Examples 1,2 and 3) haveshown an in vivo CNS functional activity, such as: feeding behavior inrats. These compounds induced an acute (1-4 h after the intraperitonealadministration at 25 mg/kg) hyperphagic effect respect to the controlgroup (7-10-fold, P<0.05), which was lower in potency than those inducedby idazoxan (10 mg/kg, i.p.) (cf Table 2: cummulative food intake (g/kgbody weight) at 1,2 and 4 hours after intraperitioneal administration ofthe compounds and the standard drug idazoxan).

However, Example 2 was equally as potent as idazoxan for the I₂-imidazoline receptors according to the data derived from bindingstudies but much more selective (cf Table 1). Also, the selectivityratio for IR/alpha₂ and IR/alpha₁ are indicated.

Thus, these compounds may have a therapeutic as appetite stimulantsand/or antianorexics. Other data obtained in different laboratories alsosupport the therapeutic potential of imidazoline drugs acting uponimidazoline receptors as appetite stimulants and/or antianorexics(Jackson et al., Br. J. Pharmacol. 1991, 104, 258-262).

The compounds of the invention have been found deprived of action onserotonin receptors.

On the other hand, an approximative LD₅₀ was obtained from the Irwintest performed in mice (4 animals, 50% males and females), wherecompounds of the invention (all at 100 mg/kg, i.p.) did not cause anydeath during 72 hours. So, the approximative intraperitoneal LD₅₀ inmice for these compounds was higher than 100 mg/kg.

In accordance to their physical, chemical and pharmaceuticalcharacteristics, these compounds may be prepared in a form suitable fororal, rectal or parenteral administration. Such oral compositions may bein the form of capsules, tablets, granules or liquid preparations suchas elixirs, syrups or suspensions.

Tablets contain a compound or a non-toxic salt thereof in admixture withexcipients which are suitable for the manufacture of tablets. Theseexcipients may be inert diluents such as calcium phosphate,microcrystalline cellulose, lactose, sucrose or dextrose; granulatingand disintegrating agents such as starch; binding agents such as starch,gelatin, polyvinylpyrrolidone or acacia; and lubricating agents such asmagnesium stearate, stearic acid or talc.

Compositions in the form of capsules may contain the compound or anon-toxic salt thereof mixed with an inert solid diluent such as calciumphosphate, lactose or kaolin in a hard gelatin capsule.

Compositions for parenteral administration may be in the form of sterileinjectable preparations such as solutions or suspensions, for example:water or saline.

For the purposes of convenience and accuracy, the compositions areadvantageously employed in a unit dosage form. For oral administrationthe unit dosage form contains from 0.5 to 300 mg, preferably 1 to 100 mgof the compounds or a non-toxic salt thereof. Parenteral unit dosageforms contain from 0.05 to 20 mg of the compounds or a non-toxic saltthereof per 1 mL of the preparation.

                  TABLE 1                                                         ______________________________________                                        Affinity (K.sub.i, nM) Selectivity                                            Compound                                                                              IR       Alpha.sub.2                                                                            Alpha.sub.1                                                                          IR/α.sub.2                                                                     IR/α.sub.1                      ______________________________________                                        Example 1                                                                              89      100 148  36 540 1 125  410                                   Example 2                                                                              15      62 061   26 169 4 137  1 744                                 Example 3                                                                             151      56 150   17 800 372    118                                   Example 6                                                                             117      68 350   33 258 584    284                                   Example 7                                                                             163      98 719    4 405 605     27                                   Example 9                                                                             123      71 320   22 615 580    184                                   Idazoxan                                                                               14      5        91     0.4    6.5                                   RX 821002                                                                             44 902   0.7      ND     0.00002                                                                              --                                    ______________________________________                                         The results are the mean of 10 experiments. RX 821002 is the methoxy          derivative of idazoxan.                                                       ND: not determined                                                       

                  TABLE 2                                                         ______________________________________                                        Com-   Dose          Time (h)                                                 pounds mg/kg   N     1         2       4                                      ______________________________________                                        Carboxy-                                                                             --      5     0.04 ± 0.01                                                                          0.2 ± .05                                                                          0.6 ± 0.1                           methyl-                                                                       cellulose                                                                     0.5%                                                                          Idazoxan                                                                             10      5     3.7 ± 1.2**                                                                          5.6 ± 2.1**                                                                        7.4 ± 2.3**                         Example                                                                              25      5     3.0 ± 2.0**                                                                          4.0 ± 2.1**                                                                        4.8 ± 2.0**                         Example                                                                              25      5     2.7 ± 1.5**                                                                          3.0 ± 1.5                                                                          3.6 ± 1.4*                          2                                                                             Example                                                                              25      5     1.3 ± 1.0*                                                                           3.4 ± 1.2*                                                                         3.8 ± 1.2*                          3                                                                             ______________________________________                                         *significant                                                                  **highly significant                                                     

I claim:
 1. Process for the preparation of benzofuranylimidazolederivatives of the formula ( 1) ##STR9## wherein R₁ represents ahydrogen atom, andR₂ represents a hydrogen atom, a halogen atom, analkyl group having from 1 to 6 carbon atoms or an alkoxy group havingfrom 1 to 5 carbon atoms;or a therapeutically acceptable salt of such aderivative, the process comprising the following successive steps:reacting a compound of formula (2) ##STR10## wherein R represents analkyl group having from 1 to 4 carbon atoms and HX represents an acid,with, at least, one molar equivalent of an aminoacetaldehyde dialkylacetal, in a polar solvent, for 1 to 24 hours, at a temperature of from-5° C. to the boiling point of the reaction mixture thereby obtaining acompound of the formula (3) ##STR11## wherein R' and R" represent, each,an alkyl group having from 1 to 4 carbon atoms, and cyclizing, in anaqueous acidic medium, for 1 to 24 hours, at a temperature of from 15°to 80° C., the compound of the formula (3), said cyclizing resulting incompounds of the formula (1).
 2. The process of claim 1 furtherincluding the process of substituting on the compound of the formula (1)a selected alkyl group having from 1 to 6 carbon atoms for the R₁hydrogen, said process comprising the steps of treatment of the compoundof the formula (1) by a base, in an aprotic solvent, at a temperature offrom -10° C. to 25° C., followed by treatment with an alkyl halide oralkyl sulfonate, said alkyl halide or alkyl sulfonate having the saidselected alkyl group.
 3. The process of claim 1 further including theprocess of substituting on the compound of the formula (1) a hydroxygroup at R₂, the process comprising selecting a compound according toformula (1) wherein R₂ is alkoxy, and treating said compound with adealkylating agent selected from the group consisting of trimethylsilyliodide and aqueous hydrogen bromide.
 4. Process according to claim 1wherein the first step is conducted for 15-17 hours in refluxingmethanol.
 5. Process according to claim 1 wherein the second step isconducted at 40°-60° C. for 16-20 hours in 10% aqueous hydrochloricacid.
 6. Process according to claim 2 wherein the first step isconducted with sodium hydride, in dimethylformamide at 0° C.